Capitalizing on 15 years of research in multiple laboratories in this area the goal of this Program Project application is to provide a comprehensive and mechanistic understanding of the cross-talk existing between bone and the brain by addressing four issues. First, the discovery that brain-derived serotonin favors bone mass accrual by inhibiting the activity of the sympathetic nervous system raises questions about the transcriptional mechanisms regulating brain serotonin accumulation and catecholamine synthesis. Second, the role played by factors coming from the mothers in the offspring brain development and cognition raises the question that a similar influence for bone mass acquisition may exist. Third, that Tph1, the initial enzyme in the synthesis of gut-derived serotonin is also needed for melatonin synthesis in pineal gland raises the question of the possible role of melatonin as a regulator of bone mass accrual. Our hypothesis is that one extracellular cue limiting the influence of the sympathetic tone on osteoblast functions could be melatonin. Fourth, if we now look at the relationship between bone and the brain from the point of view of bone, the powerful but inhibitory regulation of bone mass accrual by the brain raises the question of whether bone limits this deleterious influence by acting directly in the brain. In addressing these fundamental questions of bone biology and whole-organism physiology the laboratories of the three project leaders of this application have generated in the last five years enough preliminary data to justify their respective projects. The three major questions tackled by this Program Project are: * To determine the influences of bone remodeling via osteocalcin on the metabolic status and cognition of mice as they age. * To demonstrate that one mechanism by which the longevity-associated protein Sirtuin 1 regulates bone mass is through its functions in the brain. * To define the role of melatonin in bone remodeling during growth, aging and gonadal failure and determine whether maternal by-products of Tph1 are determinants of peak bone mass and future bone health of the offspring.